Many biological functions come about, at least in part, due to the ability of proteins to adopt various sequence-dependent structures. However, particularly, although not exclusively, with regard to neural functions, certain proteins can sometimes form aberrant, misfolded, aggregates known as amyloid oligomers and amyloid fibrils following expression of the protein. These amyloid aggregates are associated with and thought to be involved in the pathogenesis of various amyloid diseases of genetic, infectious and/or spontaneous origin, including spongiform encephalopathies, Alzheimer's disease, Parkinson's disease, type II diabetes, Creutzfeldt-Jakob disease, Huntington's disease, possibly macular degeneration, various prion diseases and numerous others. In at least some of these amyloid diseases, the formation of amyloid oligomers precedes and appear to lead to the development of amyloid fibril plaques.
Amyloid peptides are the principal constituent of amyloid plaques. In the case of Alzheimer's disease (“AD”), the peptides are termed Aβ or β-amyloid peptide. Aβ peptide is an internal proteolytic fragment of 39 to 43 amino acids of amyloid precursor protein (APP). The normal function of full-length APP is not definitively known, but it is thought to be associated with neuronal development. Aβ monomers are soluble and appear to be harmless in solution, but undergo a major conformational change at sufficiently high concentration, and thereafter form amyloid oligomers or fibrils that deposit within neurons or outside the neurons.
Several mutations within the APP protein have been correlated with the presence of AD. See, for example, Goate et al., Nature, (1991) 349, 704 (valine to isoleucine); Chartier Harlan et al., Nature (1991)353, 844 (valine to glycine); Murrell et al. Science (1991) 254, 97 (valine to phenylalanine); Mullan et al., Nature Genet. (1992) 1, 345 (a double mutation changing lysine595-methionine596 to asparagine595-leucine596). Such mutations are thought to cause AD by producing an increased or altered processing of APP to Aβ. In particular, the processing of APP resulting in accumulation of the longer forms of Aβ, for example, A1-42 and A1-43 is thought to be important in the cause of AD. Mutations in other genes, such as the presenilin genes PS1 and PS2, are thought to indirectly affect processing of APP resulting in production of the long form of Aβ. See, for example, Hardy, TINS (1997) 20, 154.
European Patent Publication EP 526,511 (McMichael) and PCT International Patent Publication WO/9927944 (Schenk) have described the administration of Aβ to patients for the treatment or prevention of Alzheimer's. However, although active immunization of Aβ to transgenic mice produces apparent benefits, the extension of this approach to AD patients has resulted in undesirable inflammation of the central nervous system in some of the subjects. See Hardy, D. J. Selkoe (2002) Science 297, 353-356.
Soluble Aβ includes Aβ monomers as well as soluble aggregations of such monomers referred to as “oligomers” or “prefibrillar oligomers” or “protofibrillar aggregates”. These oligomers or prefibrillar oligomers or protofibrillar aggregates may eventually lead to the development of amyloid fibrils. Soluble Aβ content of the human brain is better correlated with the severity of AD than is the accumulation of amyloid plaques. See, for example, Y. M. Kuo et al. (1996) J. Biol. Chem. 271, 4077-4081; C. A. McLean et al. (1999) Annals of Neurology 46, 860-6; L. F. Lue et al. (1999) American Journal of Pathology 155, 853-862. In addition, recent reports suggest that the toxicity of Aβ and other amyloidogenic proteins lies not in the soluble monomers or insoluble fibrils that accumulate, but rather in the oligomers or oligomer prefibrillar oligomer or protofibrillar aggregates. See, for example, Hartley et al. (1999), Journal of Neuroscience 19, 8876-8884; Lambert et al., Proceedings of the National Academy of Sciences of the United States of America (1998) 95, 6448-53; and Bucciantini et al., Nature (2002) 416, 507-511; and Hartley et al. Nature (2002) 418, 291. Taken together, these results indicate that the appearance of oligomers or prefibrillar oligomers or protofibrillar aggregates may be considerably more pathologically significant than of other forms of the amyloid peptides and therefore may be a more desirable target in the prevention or curing of amyloid diseases such as AD.
There is therefore a need for the development of antigens capable of producing antibodies which selectively or specifically bind to and/or sequester the toxic form of amyloid, thereby inhibiting the pathogenesis, or slowing the progression of amyloid diseases. In addition, such antigens, may be useful in designing and purifying such antibodies. Further, therapeutic agents comprising at least one such antibody may be useful and a prophylactic against the development of the symptoms of AD, such as, without limitation, loss of memory (amnesia), language impairment (aphasia), impairment of skilled movements (apraxia), recognition (agnosia) and decision making and planning functions characteristic of the frontal lobe of the brain, and well as the symptoms of other amyloid diseases.